The and can be divided into 4
The chemotherapeutic failure or on the other name chemotherapeutic resistance : is when the host cell can evade (resist) theeffects of chemotherapeutic agent. It is one of the most problem in chemotherapy.Chemotherapy resistance can be divided into 2 main factor: firstly, host -related factors. The second oneis tumor related factor, which is reflected the effect of chemotherapeutic bythe mechanism of efflux- pump that handle the expression of drug .
Host RelatedfactorsPharmacokineticis an effects of host-related factors that can determine the activity of thedrug . it is defined as the what body do to the drug and can be divided into 4situation : absorption, distribution, metabolism and excretion (ADME). The host mechanism that reflected the effective of chemotherapeutic drug, byprevent reaches its target or prevent to fulfill its intended goal is “Pharmacokinetic resistance ” . (Drugs must target the tumor site to kill themicro-organism).
Absorption: it can reduce the effect of the drug by reducing the bioavailabilityof it. Then, cause failure of drug effect this occur by permeabilityglycoprotein that found in (GIT)including the small intestine. P-gp canreflected the chemotherapeutic effect by reducing the oral bioavailability ofdrugs . this is by overexpression of P-gp that results in bioavailabilityreduction of several these agents.
Also, food is another example which can affect the drug absorptionand bioavailability. Highly fat meal can affect the drug bioavailability anddecrease the affect . Metabolism Thereare 2 steps of drug metabolism , the first step is involve reactions of hydroxylation oroxidation. metabolism enzymes such as CYP450 and glutathione S–transferasecould be lead to inactivattion certain anti- tumor drugs.
Introducing polargroups into xenobiotic groups occur by CYP450 enzyme. Overexpression of CYP450 in cancer patientsmight lead to resistance due to the rapid inactivation of the drug. GlutathioneS Trans-ferase also another enzyme thatcould contribute the resistance of chemotherapy. it responsible in the secondstep of drug metabolism, the resistance occur when overexpression of thisenzyme (same CYP450) . This resistance could occur by metabolizing the drugsinto inactive form .Excretion It is the final rotation of the drug in thebody . it can by two mechanism : biliary and renal excretion.
The change rate of glomerular filtration rate(GFR) can effect of drug availability and bioavailability which can contributeto the resistance of chemotherapeutic . Drug–drug interactions Usually , the combine of two or moreof chemotherapy is good in treat the infection. Conversely, it sometimes thatco-administration of drugs may lead to antagonism, one drug may counteract theother one. Lately, Sodiumbicarbonate has been used systemically in the treatment of cancer. By inducessystemic alkalosis, it can enhance methotrexate excretion by elevation of urinepH. Therefore, sodium bicarbonate modulates the pharmacokinetics ofmethotrexate. Tamoxifen is another drugthat can decreased their activity by drug-drug interaction .
it is a pro-drug that needs to be metabolized to itsactive form by CYP2D6 and other . Some drugs, particularly from the group ofSSRI, inhibit CYP2D6 and so reduce the efficacy of Tamoxifen by decreasingamount of its active metabolites. A combination of clindamycin and macrolidesdrug class can antagonize each other. Tumorrelated factorsSometime the failure of chemotherapyto treat associated with the tumor site. Could be by Evolutionary resistanceor acquired resistance . The resistancethat can be found in bacteria due to exposure to antibiotics is called acquired resistance. it could be either through altering its site ofaction or interfering with drug resident.
Altering drug siteit is occur when the drug reached itstarget lead to altering the site of drug which lead then to the resistance . theexample is methotrexate. It is a drug of choice for the treatment of severaltypes of tumors. The mechanism of methotrexate inhibition of the dihydrofolate reductase enzyme (DHFR) this inhibition of theDHFR lead to inhibit the tumor cells. Researches show that the DHFR can reflected themethotrexate by generating extra copy of its which means that producing more copyof dihydrofolate reductase enzyme. Also, there is another example which can reflectedtheir effect by altering the site of it. Fluorouracil which its MOA is thymidylate synthetaseinhibitor and it used in several types of tumors.
It has shown that the more production of extra copies of thatenzyme can contribute the resistance tothe drug. Alteration of drug residency incancer cellsP-glycoprotein It is a glycoproteinwhich is localized at the plasmamembrane of colon, jejunum, bilecanaliculi and the other . it is consider as enzyme inducer of CYP3A4. This expression of CYP3A4 can decreasedthe activity of some chemotherapeutic such as (cyclosporin,Tamoxifen). This isexplain the altering drug residency. Microenvironmentalresistance (Trapping mechanism) The micro environmental of thetumor can make failure to chemotherapeuticby reducing the activities of it this lead to causing fail in responses of the drug. This is by twomechanism : one of it through disturbing drug partitioning, thesecond is through induction of multidrug resistance expression. It is prevented chemotherapeutic to reaching theirtargets site .
Because the weakly acidicdrugs increase their dividing into theinterstitial fluid, which is alkaline media this prevented from reaching their targets.chemotherapy could impacted their activity and contribute in drugresistance by the physics of the tumor site. There are 2 mechanism in which Tumorcan decreased the amount of drug to reaching its target either by clonal tumorexpansion or by the tumor perfusion .This is called interacting of humor- host factor